Our proposed study is based on two recent observations made in our laboratory. The first observation is that IL-12 or cyclophosphamide (Cy) +IL-12 treatment is highly effective/curative against established large tumor burdens in mice bearing immunogenic, but not non-immunogenic, tumors. One critical factor that is required for optimal response to IL-12-based therapy is the presence of tumor-sensitized T cells in tumor-bearing hosts before start of IL-12 treatment. Since only immunogenic tumors are able to induce T cell sensitization spontaneously from their hosts upon establishment in vivo, this requirement of pre-existing immunity would explain the failure of established non-immunogenic tumors to IL-12-based therapy. The second observation is that a spontaneously derived murine metastatic breast tumor 4T1 is non-immunogenic in normal BALB/c mice and is resistant to IL-12-based therapy as expected based on the pre-existing immunity requirement. However, in STAT6 gene knockout mice 4T1 becomes immunogenic and responsive to IL-12-based immunotherapy. Based on these two observations, we hypothesize that there is a close correlation between tumor immunogenicity and response to immunotherapy and eradication of established non-immunogenic tumors by IL-12-based therapy may be improved if tumor-sensitized T cells can be raised in the host bearing non-immunogenic tumors prior to therapy. Furthermore, we hypothesize that certain host factors such as STAT6 critically influence the immunogenicity of a tumor. By manipulating these factors and their corresponding pathways, we may be able to increase T cell sensitization against non-immunogenic tumors, which would directly contribute to a better response of these tumors to immunotherapy. Our proposed study focuses on 1) confirmation of the effect of STAT6 deletion on tumor immunogenicity in multiple tumor models and different mouse strains, 2) identification of the mechanism by which STAT6 is involved in regulating tumor immunogenicity, and 3) testing the correlation between increased T cell sensitization against nonimmunogenic tumors and their response to immunotherapy. [unreadable] [unreadable]